Polymeric hyaluronic acid or its pharmaceutically acceptable salt is used to treat degenerative arthritis, rheumatoid arthritis, and their likes. Hyaluronic acid or its salt is commonly prepared in the form of a liquid injection and is administered directly to the affected joint such as the knee and the shoulder. It is reported that the viscoelastic polymer substance is directly injected into the articular cavity of an arthritis patient to relieve the shock felt upon joint movement due to the lost cartilage tissue, as well as to facilitate lubrication, thus alleviating joint pains, normalizing functions, as well as improving arthritis-caused dysfunctions and inhibiting pains. (Jeung Tak Suh, Clinical importance and application of hyaluronic acid. Korean Journal of Family Medicine 2002; 23(9): 1071-1079; Dong Chul Lee, Seung Hee Back, Wook Jin Sohn et al. Effect of the hyaluronic acid on osteoarthritis of the knee. Journal of Korean Knee Society 2002; 14(2): 213-221; Yeong Wook Song. Pharmacological therapy in osteoarthritis. Journal of Korean Medical Association 2003; 46(11): 958-964; Seung Sook No, Jae Jun Lee, Sung Mi Hwang et al. Efficacy of intra-articular sodium hyaluronate in patients with osteoarthritis of the knee. The Korean Journal of Pain 2004; 17(2): 170-174).
According to literature reports, it has been shown that administration of hyaluronic acid in combination with certain types of nonsteroidal anti-inflammatory drugs (NSAIDs) directly to the articular cavity can improve the effects of the hyaluronic acid injection. (S C Lee, D W Rha. W H Chang. Rapid analgesic onset of intra-articular hyaluronic acid with ketorolac in osteoarthritis of the knee. J. Back Musculoskeletal Rehabilitation 2011; 24:31-38).
Piroxicam, a nonsteroidal anti-inflammatory drug of the benzothiazine derivative class, produces its anti-inflammatory effect by inhibiting prostaglandin synthesis, and is currently used to treat degenerative arthritis for its outstanding analgesic and anti-inflammatory actions as well as the long plasma half-life. It has been demonstrated to show excellent topical anti-inflammatory and analgesic effects, and furthermore, it has been reported that the drug, upon direct intraarticular injection, effectively removes inflammation (Izdes S, Orhun S, Turanli S, Erkilic E, Kanbak O. The effects of preoperative inflammation on the analgesic efficacy of intraarticular piroxicam for outpatient knee arthroscopy Anesth Analg 2003; 97(4):1016-1019).
Piroxicam injections (e.g. Felaxicam injection, Dream Pharma Corp., intramuscular injection) or injections of its salts (e.g. Rheoma injection, Sam Sung Pharmaceutical Ind. Co., Ltd., intramuscular injection) currently on the market are alkaline aqueous solutions of pH 8.5 or above, and thus pose the problem of easily producing crystallization or turbidity in the pH range falling outside of the alkaline solution (due to their instability in such an environment). Moreover, direct injection of the alkaline solution of pH 8.5 or above containing piroxicam or its salt to the diseased area including joints and shoulders may induce irritation within the tissue, such as pain, inflammation, or edema.
Furthermore, hyaluronic acid is reported to exhibit decrease in molecular size and drop in viscosity upon oxidation-reduction reaction or chain hydrolysis reaction, thus requiring lightproof refrigerated storage. Particularly, it is reported that the decomposition may accelerate in a strong acidic or strong alkaline aqueous solution. Viscosity has a direct effect on the therapeutic action of hyaluronic acid or its salt; decrease in viscosity is reported to cause a rapid reduction of its pharmacological action.
For these reasons, simply adding hyaluronic acid or it salt to the intramuscular injection of the existing piroxicam or its salt and directly administering the product to the lesion poses many pharmaceutically problematic consequences. Therefore, in order to manufacture an aqueous solution of the combination of piroxicam or its salt and hyaluronic acid or its salt, a pharmaceutical composition is required that is highly compatible with both hyaluronic acid and piroxicam, and is able to improve the physicochemical stability of hyaluronic acid and piroxicam.
Korean Patent Application No. 1992-12790 discloses the injectable pharmaceutical composition of piroxicam potassium, containing piroxicam potassium, lidocaine, triethylene glycol and sterile water for injections. According to the above-identified patent application (Example 2), the drug is soluble only in the alkaline condition of pH equal to or exceeding 8.5 despite the solvent comprising 40% wt of the composition, and a pH of 7.4 or below caused a problem of formation of piroxicam potassium precipitation. Also in particular, it is pointed out that mixing sodium hyaluronate reduces the stability of hyaluronic acid.
Korean Patent Application No. 1986-4782 discloses the method of manufacturing the injections by dissolving an alkali metal salt of piroxicam in water and applying 30-80% wt of propylene glycol, polyethylene glycol, and dimethylacetamide per principal ingredient. However, dimethylacetamide included in the above-mentioned patent application is a highly toxic solvent with a margin of exposure of 10.9 mg per day and whose use at present time is strictly limited, thereby deemed problematic to administer to a diseased area.
Korean Patent Application No. 1989-8200 discloses the injectable composition comprising piroxicam and solubilizing agent of 1.1-1.2 mole of L-arginine or L-lysine, propylene glycol and povidone per 1 mole of piroxicam. The Examples 1-5 is soluble only in pH of 8.0 or above and a problem of a decrease in physical stability in pH of 7.4 or below is seen. Mixing sodium hyaluronate poses the problem of significantly decreasing the stability of hyaluronic acid.
U.S. Pat. No. 4,434,163 and European Patent No. 66458 describe allowing piroxicam to react with L-arginine, producing an arginine salt of piroxicam, and mixing the product with disodium hydrogen phosphate (Na2HPO4) to generate a vial filled with injectable powder. However, such an injectable powder, once dissolved in aqueous solution, generates crystal deposits when stored at room temperature for two or more days. This phenomenon makes its long-term storage in the liquefied form impossible, thus presenting a drawback of requiring immediate use.
Korean Patent Application No. 1985-1074 has demonstrated successfully the enhancement of solubility of piroxicam by adding cyclodextrin. However, said technique involves spray-drying or freeze-drying procedures, making it a complicated manufacturing process. Furthermore, these techniques are used to enable oral administration of piroxicam, including tablets, and possess drawbacks of generating precipitation extracts upon long-term storage in aqueous solution, as well as insufficient stability.
U.S. Pat. No. 5,646,131 and U.S. Published Application No. 2007/0270379 have successfully enhanced the solubility of piroxicam using cyclodextrin in combination with hydroxy-carboxylic acid or arginine. However, said technique is designed for oral administration of piroxicam including tablets, and possess the drawbacks of generating precipitation extracts upon long-term storage in aqueous solution as well as insufficient stability.
As shown above, the present inventor has identified that, from the existing prior art, one cannot manufacture a complex composition combining piroxicam and hyaluronic acid as active ingredients. Accordingly, in efforts to develop a stable liquid composition containing piroxicam or its pharmaceutically acceptable salt and hyaluronic acid or its pharmaceutically acceptable salt, the inventor has tested various pharmaceutically acceptable common solubilizing agents, stabilizing agents, solvents, and the likes, culminating in the completion of the present invention.